Autosomal dominant polycystic kidney disease (ADPKD), the most prevalent inherited kidney disorder, affects approximately 1 in 1,000 live births and is primarily caused by pathogenic variants of PKD1 (80%) or PKD2 [1]. Very-early-onset (VEO)-ADPKD, diagnosed in utero or within the first 18 months of life, is significantly associated with PKD1 protein-truncating or de novo variants. This condition typically presents with early kidney enlargement, rapid cyst progression, early development of hypertension, and an accelerated decline in kidney function compared to classical ADPKD [2]. Classic 21-hydroxylase deficiency (21-OHD), which accounts for approximately 95% of congenital adrenal hyperplasia (CAH) cases, occurs in approximately 1 in 15,000 births. The salt-wasting form can lead to life-threatening adrenal crises in newborns [3]. Although 21-OHD does not typically cause hypertension, glucocorticoid and mineralocorticoid replacement therapies can influence blood pressure (BP) [4]. Additionally, VEO-ADPKD independently predisposes patients to early hypertension [5]. To the best of our knowledge, this is the first reported case of VEO-ADPKD presenting concurrently with 21-OHD. In this report, we describe a newborn diagnosed with both conditions during the neonatal period, emphasizing the need for close multidisciplinary collaboration where treatment for one condition may directly affect the other.

An 8-day-old male newborn was referred for further evaluation following a markedly elevated level of 17-hydroxyprogesterone (17-OHP) at 51.4 ng/mL, detected during newborn screening. He was born at term with a birth weight of 3.49 kg and is the second child of non-consanguineous Korean parents with no family history of kidney or endocrine disorders. At the time of presentation, his height and weight were 53.5 cm and 3.31 kg (both at –0.1 standard deviation score), and his BP was 84/65 mmHg, which is appropriate for his age. Physical examination revealed hyperpigmentation of the scrotum and lips, with no signs of dehydration, and the male external genitalia appeared normal. Blood tests indicated hyperkalemia (6.5 mmol/L) and hyponatremia (129 mmol/L), with glucose levels within normal limits. Adrenocorticotropic hormone (ACTH) levels were significantly elevated at 370 pg/mL, and plasma renin activity was noted to be within the upper normal range for the patient's age, measuring 25.15 ng/mL/hr. An ACTH stimulation test demonstrated persistently elevated 17-OHP levels. The diagnosis was established on clinical and biochemical grounds. The patient was subsequently started on hydrocortisone, fludrocortisone, and oral sodium chloride supplementation (Table 1). In addition to the endocrine findings, prenatal evaluation had identified a solitary 1.3 cm cyst in the right kidney. Postnatal ultrasonography conducted at 11 days of age revealed multiple small cysts in the left kidney as well as two cysts in the right kidney (Fig. 1); both kidneys were of normal size. The liver and adrenal glands appeared unremarkable. Kidney ultrasonography in both parents revealed no abnormal findings. Kidney function and urinalysis were normal. Follow-up ultrasonography was scheduled at 3-month intervals, along with outpatient nephrology monitoring. Given the diagnosis of CAH and the presence of prenatal kidney cysts, chromosomal analysis, CYP21A2 sequencing, and a targeted cystogenesis-related gene panel were performed; detailed panel composition and methodology have been described in previous literature [6]. Chromosomal analysis revealed a karyotype of 46,XY,22pstk+, which is classified as a benign constitutional variant. Sanger sequencing of CYP21A2 identified two known variants: NM_000500.9:c.293-13C>G, classified as likely pathogenic (PS3, PM2, PP4, and PP5), and NM_000500.9:c.955C>T (p.Gln319Ter), classified as pathogenic (PVS1, PM2, and PP5), in accordance with the guidelines set forth by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Parental segregation analysis was not performed; therefore, the allelic phase could not be confirmed. To investigate cystic kidney disease, the panel identified a heterozygous truncating variant in PKD1, NM_001009944.3:c.12013C>T (p.Gln4005Ter), which has been previously reported as pathogenic (PVS1, PM2, PP4, and PP5). Neither parent exhibited the PKD1 variant, supporting a de novo occurrence. The patient remained clinically stable without experiencing an adrenal crisis while receiving hydrocortisone and fludrocortisone. Plasma renin activity and ACTH levels were within age-appropriate ranges, and no hypoglycemia or electrolyte imbalances occurred. During nephrology follow-up, a gradual increase in kidney cysts was observed, with medullary nephrocalcinosis noted at 6 months of age, which progressively worsened thereafter (Fig. 1). Nephrolithiasis (<3 mm) was subsequently identified at 5 years of age. Mild proteinuria persisted from 3 years of age (urine protein-to-creatinine ratio, 0.20–0.25 mg/mg) without significant hypercalciuria. Kidney size and BP were within normal ranges, while kidney function remained stable overall but showed a modest decrease during the 5-year evaluation (Table 1). Vitamin D supplementation was initiated for deficiency and subsequently tapered as nephrocalcinosis worsened. At 3 years and 7 months of age, the patient exhibited a persistently elevated resting BP (122/86 mmHg), classified within the stage 2 hypertension range according to the 2017 American Academy of Pediatrics guidelines, despite unchanged steroid replacement doses [7]. This prompted a kidney Doppler ultrasonography, which revealed normal resistive indices, no evidence of renovascular hypertension, and a stable cyst size. Because both VEO-ADPKD and steroid replacement could have contributed to hypertension, management required careful consideration of the conflicting therapeutic goals: reducing BP while maintaining adequate mineralocorticoid replacement for adrenal crisis prevention. Accordingly, enalapril (0.16 mg/kg daily) was initiated, and the fludrocortisone dose was reduced by half. BP subsequently improved to approximately 99/60 mmHg, enabling the discontinuation of enalapril after 6 months (Table 1). The hydrocortisone dose was increased at 5 years and 4 months of age due to progressively rising 17-OHP concentrations over the preceding months, accelerated growth velocity, and advanced bone age. Initially, androstenedione levels increased but subsequently decreased following dose adjustment. Fludrocortisone was maintained at 0.05 mg daily because continued mineralocorticoid replacement was required, and its glucocorticoid activity is minimal.

To the best of our knowledge, this is the first reported case of simultaneous VEO-ADPKD and CAH. The significance of this case lies not only in its rarity but also in the clinical complexity arising from the interaction between endocrine and kidney manifestations, necessitating coordinated multidisciplinary management.

In ADPKD, genotype-phenotype correlations are well established, and truncating PKD1 variants—such as c.12013C>T (p.Gln4005Ter) in our patient—are associated with more severe clinical manifestations and earlier progression to kidney failure than non-truncating variants [8,9]. Although most evidence is derived from adult cohorts, patients with truncating variants develop kidney failure significantly earlier compared to those with non-truncating variants (mean age: 51 years vs. 56 years) [8]. VEO-ADPKD represents an aggressive phenotype characterized by earlier cyst development, early-onset hypertension, and an accelerated decline in kidney function [2,5,10]. Regarding CAH, genotype-phenotype correlations have been well described. The CYP21A2 c.293-13C>G variant is a splice-affecting allele that significantly reduces residual 21-hydroxylase activity to less than 2% [3]. The accompanying nonsense variant, c.955C>T (p.Gln319Ter), is categorized as a group 0 null allele. The presence of two severe CYP21A2 variants was consistent with the classic salt-wasting 21-OHD phenotype, although the allelic phase was not molecularly confirmed [3].

Although classic 21-OHD does not typically cause hypertension, glucocorticoid and mineralocorticoid replacement can influence BP and intravascular volume [4], and VEO-ADPKD independently predisposes patients to early hypertension [5]. In our patient, this posed a therapeutic challenge: mineralocorticoid replacement was essential for adrenal crisis prevention, yet required careful titration to avoid exacerbating hypertension in the setting of cystic kidney disease. Reducing the fludrocortisone dose improved BP without compromising adrenal sufficiency, illustrating the importance of careful BP control for long-term cardiovascular and kidney protection. Nephrocalcinosis and nephrolithiasis in this patient were likely multifactorial rather than attributable to a single disorder. CAH-related factors, including dehydration risk, altered mineral balance, and treatment-related metabolic effects, may have contributed to medullary calcification, whereas tubular dysfunction associated with ADPKD may also have contributed to stone risk. This interpretation has practical implications for follow-up, including careful monitoring of hydration status, urinary biochemical parameters, and serial imaging findings.

This case highlights the importance of early diagnosis, genetics-guided management, and vigilant longitudinal surveillance in infants with coexisting genetic disorders requiring coordinated multidisciplinary care [5,11].